(T0930-02-14) Improvement of Mechanical Properties of MRTX0902 by Crystalline Form Selection and Particle Engineering

Purpose: Development of oral solid dosage (OSD) forms requires adequate manufacturability, processibility and stability of the active pharmaceutical ingredients (APIs) and API blend with excipients. To achieve high robustness in manufacturing process and quality of finished product, it is imperative to identify and control polymorphic form early in the development process as different forms can have significant impact on powder properties, bioavailability, and performance of the finished product. Techniques like particle engineering, co-crystal and salt formation, novel formulation manufacturing approaches have been demonstrated to result in improved mechanical properties of API and formulation blend and enable use of direct compression and continuous manufacturing over more complicated techniques [1]. Adopting a material sparing approach with development form evaluation and selection is critical as API availability is quite limited at early stages of development. This work aims to characterize the mechanical properties of MRTX0902 in relation to the freebase polymorphic forms (Type J and Type F) and corresponding fumarate salt (generation I and II). The improved powder properties of freebase Type J facilitate a rational form selection for OSD development.

Methods: Different freebase polymorphic forms (Type F and Type J) and fumarate salt of MRTX0902 were compressed on a compaction simulator (Styl’One Evolution, MedelPharm, France) simulating a Korsch XL100 compression cycle. The main compaction pressure ranged from 0.5-30kN and powder was compressed using 8mm round flat-faced punches (Natoli Engineering). External lubrication in the form of magnesium stearate spray (Styl’One MIST) was used on the die wall and punch tips before each compression cycle. Tablet hardness and dimensions were analyzed using Sotax ST50. True density was measured using Accupyc II (Micromeritrics®). Flow Function coefficient (FFc) and flowability was analyzed using Ring Shear Tester RST-XS (Dietmar Schultze). Single crystal diffraction studies were carried out on a Bruker SMART Pt135 CCD diffractometer equipped with Cu Ka radiation. The structure was solved using direct methods (SHELXT). Morphological assessment of the API forms was carried using Phenom SEM (NanoScience). Particle size determination was carried using Mastersizer 3000 (Malvern Pananalytical). The following equations were used to determine tensile strength and solid fraction of the compressed API. Fell Newton equation [2]: Tensile strength= 2F/(pi)dh where F=breaking strength of tablet (in N), d=diameter of tablet (in mm) and h=height of tablet (in mm)
Solid Fraction = Tablet density/true density

Results: Significant differences were observed between the mechanical properties of the fumarate salt and free base of MRTX0902. The two freebase forms Type F and Type J also exhibit changes in crystal packing. Compressibility, Tabletability and Compactability (CTC) of Type F, Type J and Fumarate salt (Generation I and II) of MRTX0902 reveals significant differences in the mechanical properties of free base Type J and Type F, and fumarate salt form (generation I and II). Freebase Type J and Type F both exhibited lower tabletability and compactability as compared to Fumarate salt Gen I and II, while Type J exhibits better tabletability and higher tensile strength at 100-200MPa tablet compression than Type F. Low compactability of Type F in comparison to Type J and fumarate salt form was identified as a critical factor in form selection. In addition, Fumarate salt gen I exhibited sticking to the punch tips which was significantly reduced with Gen II. Fumarate salt gen II exhibited significant improvement in CTC, sticking and flowability parameters. However, a clear disadvantage of using a salt form over freebase was addition of 30% by weight salt moiety and consequently higher tablet weight. In comparison to Fumarate salt gen II, Type J exhibited acceptable CTC, flowability and low sticking propensity. Consequently, Type J was recommended for further evaluation to identify a scalable process and formulation properties.

Conclusion: This work illustrates the relationship between mechanical properties of API and crystal forms. The difference in mechanical properties of different crystalline forms can be explained by changes in the crystal packing. Early evaluation of mechanical properties in addition to physicochemical properties enables selection of appropriate form for formulation development.

References: 1. Oisín N. Kavanagh, Chenguang Wang, Gavin M. Walker, Changquan Calvin Sun. Modulation of the powder properties of lamotrigine by crystal forms, International Journal of Pharmaceutics, Volume 595, 2021, 120274, ISSN 0378-5173
2. Fell, J.T. and Newton, J.M. Determination of tablet strength by the diametral-compression test. Volume 59, Issue 5, 1970, Pages 688-691, ISSN 0022-3549

Compressibility, Tabletability and Compactability (CTC) analysis of MRTX0902 forms

Flow-Function coefficient (FFc) of MRTX0902 forms